Desensitization is a prominent feature of most ligand-gated channels, yet its role in synaptic transmission has been difficult to ascertain. Inhibitory synaptic transmission mediated by GABAA receptors is a major target of therapeutic drug intervention for a variety of neurological disorders, thus understanding the role of desensitization in inhibitory transmission may lead to novel avenues of drug development. Recent findings indicate that a brief GABA pulse causes GABAA receptors to enter fast desensitized states that prolong the GABAA response, suggesting that fast desensitized states are critical in shaping the time course of the IPSC. Slow desensitized states of the GABAA receptor also are expected to influence inhibitory synaptic transmission by reducing the number of unoccupied receptors available for subsequent stimuli, thus providing a mechanism of use-dependent synaptic plasticity. Patch-clamp recordings of whole-cell synaptic currents, rapid agonist application to excised patches, kinetic modeling techniques and genetic mutant mice will be used to study GABAA receptor slow desensitization in cultured hippocampal neurons. The aims of this proposal are 1) to determine the kinetics of GABAA receptor slow desensitization and its contribution to short-term synaptic plasticity; 2) to characterize the conditions that promote synaptic GABAA receptor slow desensitization and 3) to examine the effect of reduced GABA release on synaptic transmission in mice that lack either glutamic acid decarboxylase (GAD)67 or GAD 65, the enzymes that synthesize GABA.